A. Keith Stewart, MB, ChB: Just to summarize where we’re at here, the meeting was characterized I think by about 7 or 8 different 4-drug combinations, mostly adding daratumumab but some others like the British one. And it seems to us that most of us are going to start using 4 drugs when the FDA allows us to, right? To be clear, daratumumab is only approved for elderly patients right now.

Infection risk and management is certainly going to be something we have to pay more attention to. So one of the values of 4 drugs has been the demonstration of deep responses, minimal residual disease [MRD] negativity. How do you define that, and what should be the threshold Adriana?

Adriana Rossi, MD: It’s very difficult to say and I think the concept of complete response [CR], what is complete, is a moving target as our tools get better.

A. Keith Stewart, MB, ChB: Yeah. You aren’t old enough, it used to be 5%.

Adriana Rossi, MD: I read about that. But practicing in New York, you know, for example, next-generation sequencing [NGS] is approved in 49 states. New York happens not to be one of them. So when you decide what methodology is better, there’s the evidence to support maybe one being superior to the other. But if you don’t have access to it or you don’t have…

Adriana Rossi, MD: Correct. One that is available to all that we could standardize.

A. Keith Stewart, MB, ChB: If it was available to you?

Adriana Rossi, MD: I could look forward...

A. Keith Stewart, MB, ChB: Do you think it should be 10 to minus 4, minus 5, minus 6?

Adriana Rossi, MD: I think as deep as we can go. So if we can reach 10 to the minus 6 in everyone, that would absolutely be a good place to be.

A. Keith Stewart, MB, ChB: Tom, your group has been pioneers in using next-generation sequencing in your patients. I think I saw that you tested 170 patients the other day. Tell us a little bit about your experience.

Thomas Martin, MD: Yes, so we’ve been using next-generation sequencing for MRD testing for quite a long time now. We also send samples to the Mayo Clinic for EuroFlow. So we’ve had experience with both. I will say that for us MRD negativity is 10 to the minus 6. I still think in every study, if you look at 10 to minus 4th MRD negativity, you see relapses and you see any tics in the road. We do 10 to the minus 5th and you see relapses and less tics in the road. If you do 10 to the minus 6th, there’s where you’re going to get some people that are really long-term progression-free survivors, which that’s really the goal that we’re trying to...

A. Keith Stewart, MB, ChB: In your opinion is this now the goal of care, the MRD negativity?

Thomas Martin, MD: I think so. But in the transplant eligible or the young fit patients, I really treat them aggressively to try to induce MRD negativity. And we use next-generation sequencing for all those patients.

A. Keith Stewart, MB, ChB: What about over at this side of the table?

Rafael Fonseca, MD: As you know, we have been using it. I think we’re dancing around the issue. I’ve said that 3 times already at this meeting. MRD is clearly the goal. The Spanish have shown that all this classification of PR/VGPR is just not going to make exercise. You know if you have a CR MRD-positive, you might as well get a PR [partial response]. So we need more data, but I think it’s very clear that that should be the benchmark. So future clinical trials need to have that as a primary endpoint. As you know we’re doing it at day 100, and it’s an important factor in how we talk to patients about prognosis, but the other use of that, which I think is quite interesting, is sort of duration of therapy, and that’s where we’re using it in sustain CRs. There are patients where you’re on the fence – should they continue on therapy or not? They’re having adverse effects. So you just bring an extra piece of information to the conversation as you try to make that decision.

Faith Davies, MD, MBBCh, MRCP, FRCPath: So you use it for stopping therapy?

Rafael Fonseca, MD: We have. I have.

Faith Davies, MD, MBBCh, MRCP, FRCPath: Because I have a tendency in that setting to maybe actually use it to escalate therapy rather than stop therapy. Stopping therapy worries me.

Rafael Fonseca, MD: I think you’re absolutely right. But if you have someone who’s on a sustained CR, who you may already be in the need of a decision of whether you continue or not because of how the patient is feeling or because of particular toxicities, this is just one more bit of information. So it is not directive 100%, but it’s one more bit of information. So the person is nervous, and, you know, I have to tell you, I have a couple of patients, high-risk 3 years out from stem cell transplant, MRD is 0, having significant toxicity, who are nervous about stopping it. I think that gives them a little bit of extra insurance. Will we have phase III data for that? Probably not.

A. Keith Stewart, MB, ChB: Are you using MRD testing, Faith, in Arkansas?

Faith Davies, MD, MBBCh, MRCP, FRCPath: Yeah. I think some of the really interesting data is, as you said, if you’re high risk and you’re not MRD positive, then we know that those patients perform really badly. And so, for those patients I’m either going to be changing therapy or escalating therapy, because I know that they’re a real poor…

A. Keith Stewart, MB, ChB: Yeah, I think this is a de-escalation question. What will you tell the community doctors? I mean it’s not easy to get MRD testing done today. They just have to make sure that their patients get it done at a center that can perform it, or is there a way they can access it through NGS?

Thomas Martin, MD: For the community doctor, it’s probably not really ready for prime time, because what do they do when they get that information? I think it’s on us. We need to show that in a clinical trial, at the time points, like Rafael said, 100 days post transplant, 1 year post transplant, 2 years post transplant, they’re MRD positive or negative, what change are we going to make? And what change in the patient’s PFS [progression-free survival] and overall survival is it going to make? Once we have those data, the community doctor should do it routinely.

Adriana Rossi, MD: And establish guidelines for when. You know, what are the time points? Right now, our practice is to send it when we do a biopsy, but we’re not doing it necessarily on a patient who’s not on study for sustainability of MRD, which I think is ultimately the goal.

Transcript Edited for Clarity

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Transcript:

A. Keith Stewart, MB, ChB: Just to summarize where we’re at here, the meeting was characterized I think by about 7 or 8 different 4-drug combinations, mostly adding daratumumab but some others like the British one. And it seems to us that most of us are going to start using 4 drugs when the FDA allows us to, right? To be clear, daratumumab is only approved for elderly patients right now.

Infection risk and management is certainly going to be something we have to pay more attention to. So one of the values of 4 drugs has been the demonstration of deep responses, minimal residual disease [MRD] negativity. How do you define that, and what should be the threshold Adriana?

Adriana Rossi, MD: It’s very difficult to say and I think the concept of complete response [CR], what is complete, is a moving target as our tools get better.

A. Keith Stewart, MB, ChB: Yeah. You aren’t old enough, it used to be 5%.

Adriana Rossi, MD: I read about that. But practicing in New York, you know, for example, next-generation sequencing [NGS] is approved in 49 states. New York happens not to be one of them. So when you decide what methodology is better, there’s the evidence to support maybe one being superior to the other. But if you don’t have access to it or you don’t have…

Adriana Rossi, MD: Correct. One that is available to all that we could standardize.

A. Keith Stewart, MB, ChB: If it was available to you?

Adriana Rossi, MD: I could look forward...

A. Keith Stewart, MB, ChB: Do you think it should be 10 to minus 4, minus 5, minus 6?

Adriana Rossi, MD: I think as deep as we can go. So if we can reach 10 to the minus 6 in everyone, that would absolutely be a good place to be.

A. Keith Stewart, MB, ChB: Tom, your group has been pioneers in using next-generation sequencing in your patients. I think I saw that you tested 170 patients the other day. Tell us a little bit about your experience.

Thomas Martin, MD: Yes, so we’ve been using next-generation sequencing for MRD testing for quite a long time now. We also send samples to the Mayo Clinic for EuroFlow. So we’ve had experience with both. I will say that for us MRD negativity is 10 to the minus 6. I still think in every study, if you look at 10 to minus 4th MRD negativity, you see relapses and you see any tics in the road. We do 10 to the minus 5th and you see relapses and less tics in the road. If you do 10 to the minus 6th, there’s where you’re going to get some people that are really long-term progression-free survivors, which that’s really the goal that we’re trying to...

A. Keith Stewart, MB, ChB: In your opinion is this now the goal of care, the MRD negativity?

Thomas Martin, MD: I think so. But in the transplant eligible or the young fit patients, I really treat them aggressively to try to induce MRD negativity. And we use next-generation sequencing for all those patients.

A. Keith Stewart, MB, ChB: What about over at this side of the table?

Rafael Fonseca, MD: As you know, we have been using it. I think we’re dancing around the issue. I’ve said that 3 times already at this meeting. MRD is clearly the goal. The Spanish have shown that all this classification of PR/VGPR is just not going to make exercise. You know if you have a CR MRD-positive, you might as well get a PR [partial response]. So we need more data, but I think it’s very clear that that should be the benchmark. So future clinical trials need to have that as a primary endpoint. As you know we’re doing it at day 100, and it’s an important factor in how we talk to patients about prognosis, but the other use of that, which I think is quite interesting, is sort of duration of therapy, and that’s where we’re using it in sustain CRs. There are patients where you’re on the fence – should they continue on therapy or not? They’re having adverse effects. So you just bring an extra piece of information to the conversation as you try to make that decision.

Faith Davies, MD, MBBCh, MRCP, FRCPath: So you use it for stopping therapy?

Rafael Fonseca, MD: We have. I have.

Faith Davies, MD, MBBCh, MRCP, FRCPath: Because I have a tendency in that setting to maybe actually use it to escalate therapy rather than stop therapy. Stopping therapy worries me.

Rafael Fonseca, MD: I think you’re absolutely right. But if you have someone who’s on a sustained CR, who you may already be in the need of a decision of whether you continue or not because of how the patient is feeling or because of particular toxicities, this is just one more bit of information. So it is not directive 100%, but it’s one more bit of information. So the person is nervous, and, you know, I have to tell you, I have a couple of patients, high-risk 3 years out from stem cell transplant, MRD is 0, having significant toxicity, who are nervous about stopping it. I think that gives them a little bit of extra insurance. Will we have phase III data for that? Probably not.

A. Keith Stewart, MB, ChB: Are you using MRD testing, Faith, in Arkansas?

Faith Davies, MD, MBBCh, MRCP, FRCPath: Yeah. I think some of the really interesting data is, as you said, if you’re high risk and you’re not MRD positive, then we know that those patients perform really badly. And so, for those patients I’m either going to be changing therapy or escalating therapy, because I know that they’re a real poor…

A. Keith Stewart, MB, ChB: Yeah, I think this is a de-escalation question. What will you tell the community doctors? I mean it’s not easy to get MRD testing done today. They just have to make sure that their patients get it done at a center that can perform it, or is there a way they can access it through NGS?

Thomas Martin, MD: For the community doctor, it’s probably not really ready for prime time, because what do they do when they get that information? I think it’s on us. We need to show that in a clinical trial, at the time points, like Rafael said, 100 days post transplant, 1 year post transplant, 2 years post transplant, they’re MRD positive or negative, what change are we going to make? And what change in the patient’s PFS [progression-free survival] and overall survival is it going to make? Once we have those data, the community doctor should do it routinely.

Adriana Rossi, MD: And establish guidelines for when. You know, what are the time points? Right now, our practice is to send it when we do a biopsy, but we’re not doing it necessarily on a patient who’s not on study for sustainability of MRD, which I think is ultimately the goal.